This is the third competing proposal submitted for In Vivo Cellular and Molecular Imaging Center (ICMIC) PSO funding from Memorial Sloan-Kettering Cancer Center (ICMIC-3). ICMIC-3 seeks to continue the productivity of ICMICs-1 and-2 for advancing Molecular Imaging (Ml) in cancer. ICMICs-1 and -2 led to new tools for Ml and the discovery of novel features of cancer biology, as described in 125 original research papers; including development of 5 novel gene expression imaging (GEI) vectors, 10 new radiotracers, including 3 T-cell tracers; 5 FDA IND's and 6 clinical protocols. Our vision for ICMIC-3 is cancer biology integrated with real-time, noninvasive imaging for application in individual patient care and management. Our research plan includes 4 Research Projects (RP's: RP1 Imaging T-cell Targeting and Function in Human Cancer; RP2 Oncogene Induced Changes in Metabolism; RP3 Imaging the Effects of Oncoprotein-Targeted Inhibitors on Tumor Growth and Metabolism; and RP4 Refining Antiandrogen Therapy for Prostate Cancer through Positron-Emission-Tomography); 2 Developmental Projects (DPs; DP-A Radiolabeling of HSP90 Inhibitors for Small Animal In Vivo Brain Imaging of Glioblastoma Multiforme; DP-B Imaging mesothelin chimeric receptor T-cell targeting in mesothelioma); and, 3 Specialized Resources (SRs; Chemistry & Radiochemistry, Gene Transfer and Quantitative Imaging). The ICMIC-3 research plan leverages the most innovative and clinically relevant prior discoveries/ developments and includes: RP1: GMP production of chimeric T-cells which target PSMA, an antigen in prostate cancer, based on GEI, for imaging in man (Ponomarev/Blasberg); RP2: multimodality metabolomic imaging with novel MRI/S and PET technology (Koutcher); RP3; pharmacologic dissection of the biology and clinical benefit of inhibiting the PI3K and Ras/ERK signal transduction pathways in melanoma and thyroid cancer (Rosen/Santos); RP4: genome wide RNA profiling for discovery of molecular determines of Ml androgen receptor targeting and glycolysis, through the use of novel mouse models of prostate cancer, and novel AR inhibitor drugs (Mellinghoff/Sawyers/Larson); DP-A: development of true tracers for Purine-based HSP90 inhibitors which cross blood brain barrier in glioma (Chiosis/Mellinghoff/Lewis); and DP-B: Chimeric T-cells with tumoricidal and targeting properties for mesothelin in mesothelioma (Sadelain/Riviere). In summary, we have shaped ICMIC-3 to closely adhere to the goals of PAR 09-157.